Retrospective and Prospective Human Intravenous and Oral Pharmacokinetic Projection of Dipeptidyl peptidase-IV Inhibitors Using Simple Allometric Principles - Case Studies of ABT-279, ABT-341, Alogliptin, Carmegliptin, Sitagliptin and Vildagliptin

• Main Authors: Ravindranath R Gilibili (Author), Ravi Kanth Bhamidipati (Author), Ramesh Mullangi (Author), Nuggehally R Srinivas (Author)
• Format: Book
• Published: Frontiers Media S.A., 2015-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Purpose: The purpose of this exercise was to explore the utility of allometric scaling approach for the prediction of intravenous and oral pharmacokinetics of six dipeptidy peptidase-IV (DPP-IV) inhibitors viz. ABT-279, ABT-341, alogliptin, carmegliptin, sitagliptin and vildagliptin. Methods: The availability of intravenous and oral pharmacokinetic data in animals enabled the allometry scaling of 6 DPP-IV inhibitors.  The relationship between the main pharmacokinetic parameters [viz. volume of distribution (Vd) and clearance (CL)] and body weight was studied across three or four mammalian species, using double logarithmic plots to predict the human pharmacokinetic parameters of CL and Vd using simple allometry.  Results: A simply allometry relationship: Y = aWb was found to be adequate for the prediction of intravenous and oral human clearance/volume of distribution for DPP-IV inhibitors. The allometric equations for alogliptin, carmegliptin, sitagliptin, vildagliptin, ABT-279 and ABT-341 were 1.867W0.780, 1.170W0.756, 2.020W0.529, 1.959 W0.847, 0.672 W1.016, 1.077W 0.649, respectively, to predict intravenous clearance (CL) and the corresponding equations to predict intravenous volume of distribution (Vd) were: 3.313W0.987, 6.096W0.992, 7.140W0.805, 2.742W0.941, 1.299W0.695 and 5.370W0.803.  With the exception of a few discordant values the exponent rule appeared to hold for CL (0.75) and Vd (1.0) for the predictions of various DPP-IV inhibitors.  Regardless of the routes, the predicted values were within 2-3 fold of observed values and intravenous allometry was better than oral allometry.  Conclusion: Simple allometry retrospectively predicted with reasonable accuracy the human reported values of gliptins and could be used as a prospective tool for this class of drugs.   This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Item Description

10.18433/J3TK55
1482-1826